Defining the Mechanism of Alpha-synuclein Dependent Restriction of Viral Neuroinvasion

定义α-突触核蛋白依赖性限制病毒神经侵袭的机制

• 批准号: 9349196
• 负责人: John David Beckham
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349196
• 关键词: Acute; Age; Americas; Antiviral Agents; Biological Assay; Brain; Brain Diseases; Brain region; Data; Diffuse; Disease; Disease Marker; Foundations; Growth; Health; Health Benefit; Herpesvirus 1; Human; Immune response; Immunohistochemistry; Immunoprecipitation; Individual; Infection; Innate Immune Response; Knock-out; Knockout Mice; Laboratories; Lewy Bodies; Lewy Body Dementia; Location; Measures; Membrane; Military Personnel; Molecular Virology; Mus; Mutation; Mutation Analysis; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neurovirology; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Phosphorylation; Polymerase Chain Reaction; Population; Populations at Risk; Positioning Attribute; Post-Translational Protein Processing; Prevention; Process; Proteins; Publishing; Research; Research Proposals; Risk; Role; Route; Serine; Site; Techniques; Time; Tissues; Transgenic Mice; Transgenic Organisms; United States; Veterans; Viral; Viral Antigens; Virus; Virus Diseases; Virus Replication; West Nile viral infection; West Nile virus; Work; alpha synuclein; brain tissue; gastrointestinal; immunocytochemistry; improved; insight; mortality; mouse model; novel; novel strategies; olfactory bulb; prevent; response; synucleinopathy

Alpha-synuclein (syn) is a neuron-specific protein known to cause Parkinson’s disease. The protein is always expressed and recent work has shown that syn mis-folds into fibrils in peripheral neurons in the gastrointestinal track and the olfactory bulb. These fibrils then spread to the central nervous system in select individuals resulting in neurodegenerative diseases like Parkinson’s disease or Diffuse Lewy Body Dementia. Veteran populations are at risk for developing neurodegenerative diseases as they age and work to understand the cause of Parkinson’s disease will yield new approaches to treat and prevent neurodegenerative diseases. We have discovered that virus infections initiate post-translational modifications of syn that are associated with Parkinson’s disease. Moreover, our prior work has shown that syn functions to inhibit virus infections from spreading from the peripheral nerves to the central nervous system. Taken together, our findings reveal a stunning new understanding of the role of syn in the brain. We hypothesize that viral infections induce post-translational modifications in syn as an antiviral mechanism. While this response is acutely protective, exposure increases the risk of syn-induced pathology that can result in long term neurodegenerative diseases found in Parkinson’s disease. We will evaluate our hypothesis by defining the mechanism of syn-induced inhibition of WNV infection in neurons and defining the interactions between syn post-translational modifications and α-syn fibril spread. We will utilize techniques in molecular virology in combination with established mouse models in the field of Parkinson’s research to define the specific interactions and consequences of the interactions between syn and viral infection in the brain. If the proposed studies are completed as outlined, we will provide novel data that will have significant impact on the field of Parkinson’s disease research and neurovirology. Thus, our proposed work will have significant benefits for our veteran populations by improving health and providing potential new approaches to prevent and treat neurodegenerative processes like Parkinson’s disease.

α-突触核蛋白（Alpha-synuclein）是一种神经元特异性蛋白质，已知会导致帕金森病。蛋白质总是 最近的研究表明，在神经元中，突触素错误折叠成外周神经元中的纤维。 胃肠道和嗅球这些纤维然后扩散到中枢神经系统， 导致神经退行性疾病如帕金森病或弥漫性路易体痴呆的个体。 退伍军人群体在发展神经退行性疾病的风险，因为他们的年龄和工作， 了解帕金森病的原因将产生新的方法来治疗和预防神经退行性疾病 疾病我们已经发现，病毒感染启动了翻译后修饰的pepsyn， 与帕金森氏症有关。此外，我们先前的工作表明，Bissyn功能抑制病毒， 感染从周围神经扩散到中枢神经系统。 总的来说，我们的发现揭示了一个惊人的新的理解的作用，在大脑中的突触。我们 假设病毒感染诱导了作为抗病毒机制的利多卡因的翻译后修饰。 虽然这种反应是急性保护性的，但暴露会增加帕金森病诱导病理的风险， 导致帕金森病中发现的长期神经退行性疾病。我们将评估我们的假设 通过定义突触素诱导的神经元中WNV感染抑制的机制， α-syn翻译后修饰和α-syn原纤维扩散之间的关系。我们将利用分子技术 病毒学结合帕金森病研究领域建立的小鼠模型， 特定的相互作用和后果之间的相互作用，在大脑中的病毒感染。如果 建议的研究完成概述，我们将提供新的数据，将有重大影响， 帕金森病研究和神经病毒学领域。因此，我们提出的工作将有重大的好处， 为我们的退伍军人群体，通过改善健康和提供潜在的新方法来预防和治疗 神经退行性疾病如帕金森病